Oligodendrocyte Dynamics in the Healthy Adult CNS: Evidence for Myelin Remodeling

In the paper

“Oligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood.”

• Also stated in: § Introduction · plain

  “However, OPs continue to divide and generate new-myelinating OLs well into adulthood (Dimou et al., 2008; Rivers et al., 2008; Psachoulia et al., 2009; Kang et al., 2010; Zhu et al., 2011; reviewed by Richardson et al., 2011).”

What the sources say

• Partly supported

  The ‘Adult generation of mature oligodendrocytes in the WM’ section reports continued generation of myelinating oligodendrocytes in adult mouse cortical white matter, including at six months. The ‘Mechanisms mediating distinct progeny’ section says gray-matter progenitors proliferate more slowly and that the few oligodendrocytes they generate do not acquire myelinating characteristics. The unqualified claim therefore extends the white-matter finding to oligodendrocyte precursors generally. (LLM, conf=0.85)

  cites Dimou et al., 2008 sourceExperimental — accuracy not yet measured
• Supported

  The Discussion’s “Adult myelinogenesis” section reports that adult oligodendrocyte precursors divide and that the authors’ experiments show they generate myelin-forming oligodendrocytes, particularly in the mouse corpus callosum. It also reports new oligodendrocytes forming over seven months after postnatal day 45. (LLM, conf=0.93)

  cites Rivers et al., 2008 source
• Supported

  The Results (page not available in our copy) report that new oligodendrocytes continue to arise from NG2 cells after eight months of age. The Discussion describes NG2-cell division and oligodendrocyte production in adult mice, while the Introduction identifies production of new myelinating oligodendrocytes in white matter as a function of adult NG2 cells. (LLM, conf=0.93)

  cites Psachoulia et al., 2009 source

In the paper

“Because the number-density of OPs within a given region does not change much with age (Rivers et al., 2008), it follows that half of the daughters of OP divisions must either differentiate (and lose OP markers) or die.”

What the sources say

• Supported

  The Results section (‘Cycling and noncycling subpopulations of adult OLPs’) reports that PDGFRA+ cell counts per unit area in the cortex and corpus callosum did not change significantly between P45 and P135. It also explicitly infers that, because the corpus callosum population does not increase despite division, half the daughters must die or differentiate and downregulate PDGFRA. (LLM, conf=0.93)

  cites Rivers et al., 2008 source

In the paper

“A short time later (P120+7), 19.9% ± 3.2% of all optic nerve OPs (defined by NG2 immunolabeling) were YFP labeled (mean ±SD, n = 3 mice), less than in the adult corpus callosum (∼45%; Rivers et al., 2008) or spinal cord (∼39%; Zawadzka et al., 2010; Tripathi et al., 2010).”

What the sources say

• Supported

  Rivers et al. is cited for the approximately 45% figure in the adult corpus callosum, not for the optic-nerve or spinal-cord figures. The Results section (‘Extensive myelin genesis in adult white matter’) reports that approximately 45% of oligodendrocyte lineage progenitors were YFP-labeled at P45 in the corpus-callosum analysis. (LLM, conf=0.94)

  cites Rivers et al., 2008 source
• Partly supported

  The Results section, “Efficient Labeling of PDGFRA-Expressing Cells after Lysolecithin-Induced Demyelination” (page unavailable), reports approximately 39% YFP labeling in spinal cord precursor cells. That figure is the fraction of PDGFRA-positive cells in a demyelinated lesion, not a measurement of NG2-defined OPs in unlesioned adult spinal cord. This citation does not support the optic-nerve or corpus-callosum figures, which the sentence attributes elsewhere. (LLM, conf=0.86)

  cites Zawadzka et al., 2010 sourceExperimental — accuracy not yet measured
• Partly supported

  The Materials and Methods section (Induction of EAE; page unavailable) reports that about 30% of spinal-cord PDGFRA+ cells became YFP+, compared with about 45–50% in the adult forebrain. This supports the regional comparison but not the cited ∼39% spinal-cord figure, and the paper measures PDGFRA+ rather than NG2-immunolabeled cells for that comparison. The 19.9% optic-nerve result is presented as the citing authors’ own finding, not as a result attributed to Tripathi et al. (LLM, conf=0.87)

  cites Tripathi et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“Now, by cumulative labeling with EdU (which does not require antigen retrieval), we are able to label all OPs throughout the adult CNS (GF≈100%), indicating that all OPs are capable of undergoing cell division (Clarke et al., 2012; this paper).”

What the sources say

• Partly supported

  The Results section reports that cumulative EdU labeling marked >98% of OPCs in the anterior piriform cortex of mice labeled from P60 and concludes that these OPCs are mitotically active. The Methods section also states that EdU detection does not require antigen retrieval. The paper does not establish a growth fraction of approximately 100% throughout the entire adult CNS; its observations concern selected mouse brain regions. (LLM, conf=0.88)

  cites Clarke et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“In the developing neocortex, ∼20% of premyelinating OLs die between P7 and P11 (Trapp et al., 1997).”

What the sources say

• Partly supported

  The Results section reports that approximately 20% of premyelinating oligodendrocytes in the developing cerebral cortex were degenerating at observations between P7 and P21. It does not establish that 20% died specifically between P7 and P11; the Discussion says the incidence of death cannot be determined without knowing how long degeneration remains detectable. (LLM, conf=0.88)

  cites Trapp et al., 1997 sourceExperimental — accuracy not yet measured

In the paper

“Recently, it has been shown that the social conditions experienced by mice can influence the morphological complexity of their OLs (including the number of internodes per OL) and that this is mediated by Neuregulin signaling through ErbB3 receptors on OLs (Makinodan et al., 2012).”

What the sources say

• Partly supported

  The paper reports that juvenile social isolation produced simpler oligodendrocytes with fewer internodes in the mouse medial prefrontal cortex (main text, Fig. 1; page unavailable). It links these effects to neuregulin-1/ErbB3 signaling, but says that pathway accounts for them 'at least in part' and does not rule out other mechanisms. The claim omits that qualification and the regional and developmental limits of the findings. (LLM, conf=0.85)

  cites Makinodan et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

“Our data are consistent with the observations that abnormally short myelin internodes accumulate with age in mouse spinal cord white matter (Lasiene et al., 2009) and that paranode frequency increases with age in the rhesus monkey brain (reviewed by Peters and Kemper, 2012).”

What the sources say

• Supported

  The Results section (“Internode length changes in aging mice”; page not provided) reports that internodes shorter than 100 μm became more frequent in older mice and were not observed in 2.5-month-old mice. This supports the mouse spinal-cord claim attributed to Lasiene et al.; the rhesus-monkey claim is attached to a different citation. (LLM, conf=0.93)

  cites Lasiene et al., 2009 source
• Supported

  The review’s “Structures That Change With Age” section reports that paranodal profiles are more frequent in old than in young rhesus monkeys. Its “Summary with Conclusions” states that paranodes are 1.2–1.9 times more common in old monkeys. Page numbers were not provided in the passages. (LLM, conf=0.94)

  cites Peters and Kemper, 2012 source

In the paper

“It is well documented that myelin formed during repair of experimental demyelination or during demyelinating injury or disease is thinner on average (larger g-ratio) than myelin that is formed during normal development (e.g., Lasiene et al., 2008), although this is less pronounced for smaller-diameter axons such as those in the optic nerve (Stidworthy et al., 2003).”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Lasiene et al., 2008 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Stidworthy et al., 2003 source

In the paper

“Consistent with this, simulations published by Lasiene et al. (2009), assuming the existence of a periaxonal space, predicted that shorter internodes should decrease conduction speed.”

What the sources say

• Partly supported

  The Discussion says that shorter internodes can change conduction speed and signal timing. It does not say the change is a decrease, and the paper’s internode measurements are not simulations; the searched passages also do not describe an assumed periaxonal space. The claim therefore attributes a more specific prediction and method to this paper than our copy supports. (LLM, conf=0.85)

  cites Lasiene et al. (2009) sourceExperimental — accuracy not yet measured

In the paper

“For example, at P60+42, 61% ± 3% of YFP+ cells in the spinal cord white matter were Pdgfra+ and 41% ± 3% were CC1+.”

In the paper

“At P60+37, mGFP+ cells in the corpus callosum had small, spherical cell bodies with numerous rod-like processes that ran parallel to each other in the direction of the axons (Figure 4B).”

In the paper

“In the gray matter (motor cortex), TC was longer (∼19 days at P21 and ∼36 days at P60) (Figure 1D–1G).”

In the paper

“In the spinal cord gray matter, 61% ± 5% were Pdgfra+ and 34% ± 6% were CC1+.”

In the paper

“In forebrain white matter (corpus callosum), TC was ∼3 days at P21 and ∼10 days at P60 (Figure 1A–1C and 1G; Table 1).”

In the paper

“TC was also longer in P60 cortical gray matter (∼36 days) than in spinal cord gray matter (∼27 days).”

In the paper

“In the motor cortex, the cell processes were less dense, less numerous, and more randomly oriented but myelin profiles were still evident (Figure 4A).”

In the paper

“Cell-cycle time was not the same in all white matter regions; at P60, TC was ∼10 days in corpus callosum, ∼15 days in spinal cord white matter, and ∼20 days in optic nerve (Table 1).”

In the paper

“Tandem pairs of mGFP+ internodes were not observed, indicating that individual late-born OLs do not synthesize adjacent internodes along the same axon.”

In the paper

“There were no significant differences in either the number of internodes per OL (21 ± 8 at P50+30, 27 ± 6 at P50+65; mean ±SD, n = 10 OLs at each age) or their average lengths (40 ± 3 μm at P50+30, 44 ± 4 μm at P50+65; means ±SEM, n > 140 internodes) (Figure 6).”

In the paper

“In the present study, we show that TC increases with age not only in the cortical gray and white matter but also in the spinal cord gray and white matter and in the optic nerve (Table 1).”

In the paper

“All mGFP+ cells were Olig2+, a few of which were NG2+ (Stallcup and Beasley, 1987), indicating that they were all OL lineage cells (Figure S3).”

In the paper

“No mGFP+ cells in the cortex or corpus callosum were NeuN+, suggesting that Pdgfra+ OPs in these regions do not generate neurons (Figure S3).”

In the paper

“For example, we now recalculate TC in the cortical gray matter of P60 mice to be ∼36 days, in close agreement with a recent estimate of ∼37 days in 2- to 3-month-old mice (Simon et al., 2011).”

What the sources say

• ?Not checked — no full text of the sourcecites Simon et al., 2011 source

In the paper

“OLs born after P120 elaborated ∼77 internodes per cell of mean length ∼22 μm”

In the paper

“Since in one experiment we counted 144 (GFP+, Caspr+) paranodes, none of which flanked the same node”

In the paper

“Transverse (end-on) views of OLs showed that their internodes were distributed more or less uniformly within a cylindrical field centered on the cell soma.”

In the paper

“We conclude that adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths.”

In the paper

“Axon caliber increases following initial myelination, presumably as a result of myelination (Foster et al., 1982), but a further increase in the diameter of myelinated axons over the longer term, as observed here, has not previously been reported for the mouse optic nerve (Dangata et al., 1996).”

What the sources say

• ?Not checked — no full text of the sourcecites Foster et al., 1982 source

In the paper

“Cell-intrinsic differences in the proliferative properties of OPs from different CNS regions have also been reported (Power et al., 2002).”

What the sources say

• ?Not checked — no full text of the sourcecites Power et al., 2002 source

In the paper

“In the rat optic nerve, the peak time of OL generation is ∼P10–P20 and ∼85% of axons are myelinated by P28 (Skoff et al., 1969).”

What the sources say

• ?Not checked — no full text of the sourcecites Skoff et al., 1969 source

In the paper

“It has been estimated that ∼50% of OLs in the perinatal optic nerve die soon after they are formed (Barres et al., 1992).”

What the sources say

• ?Not checked — no full text of the sourcecites Barres et al., 1992 source

In the paper

“For example, in the P60 corpus callosum, the OP cell-cycle time (TC) is ∼9.5 days (Table 1), implying that a number of new cells equal to the starting population must be formed within 9.5 days (because all OPs are dividing).”

In the paper

“We now accept that our previous estimate of GF≈50% was too low, possibly reflecting suboptimal antigen retrieval or inhibition of cell division by BrdU (see Figure S2).”

In the paper

“Against this idea, we showed previously that an important neuron-derived OP mitogen, platelet-derived growth factor (A-chain homodimers, Pdgf-AA), is released from neuronal cell bodies in the retina but not from their axons in the optic nerve (Fruttiger et al., 2000).”

What the sources say

• ?Not checked — no full text of the sourcecites Fruttiger et al., 2000 source

In the paper

“The fact that there are many more unmyelinated axons in the adult corpus callosum (TC ≈10 days) than in the optic nerve (TC ≈20 days) suggests that the local density of unmyelinated axons might be one factor that influences local proliferation rates, perhaps because mitogens are released from or associated with the surfaces of unmyelinated axons.”

In the paper

“so ∼4% of newly formed OLs should also be mGFP+ (because on average one new OL and one replacement OP is formed for every OP division)”

In the paper

“EdU (Invitrogen) was dissolved in the drinking water at 0.2 mg/ml, which we had determined to be nontoxic (Figures S1 and S2).”

In the paper

“However, our observations contradicted this prediction; we found that ∼6.5% of CC1+-differentiated OLs in the optic nerve were generated between P120 and P185, so there are many more adult-born OLs than would be required to myelinate the ∼1% of axons that remain unmyelinated at that age, given that late-generated OLs synthesize as much or more myelin sheath as those born earlier (see next parag”

In the paper

“Butt et al. (1994) measured randomly selected, dye-injected OLs in optic nerves from mice aged between P30 and P60, and counted ∼19 internodes per cell with an average length ∼138 μm.”

What the sources say

• ?Not checked — no full text of the sourcecites Butt et al. (1994) source

In the paper

“Internode length and the number of internodes elaborated per OL vary greatly between CNS regions (Butt et al., 1994; Murtie et al., 2007; Chong et al., 2012)”

What the sources say

• ?Not checked — no full text of the sourcecites Butt et al., 1994 source
• ?Not checked — no full text of the sourcecites Murtie et al., 2007 source
• ?Not checked — no full text of the sourcecites Chong et al., 2012 source

In the paper

“if new internodes are laid down in pairs, then each one of the pair must come from a separate OL.”

In the paper

“We calculated the required correction (for r < T < 2r) to be 3πT/(3πT-4r) ≈1.42 for P30+30, 1.50 for P50+30/65, and 1.64 for P120+65 (Figure S4).”